title: Spinobulbar muscular atrophy: polyglutamine-expanded androgen receptor is proteolytically resistant in vitro and processed abnormally in transfected cells.
abstract: The neuronotoxicity of genes with expanded CAG repeats is most likely mediated by their respective polyglutamine (Gln)-expanded gene products. Gln- expanded portions of these products may be sufficient, or necessary, for pathogenesis. We tested whether a Gln-expanded human androgen receptor (AR) is structurally altered, so that it allows for the proteolytic generation of a potentially pathogenic portion that may be resistant to further degradation. We found, in vitro , that a Gln-expanded AR is more proteolytically resistant than normal, and that it yields a distinct set of Gln-expanded fragments even after extended proteolysis in the presence of 2 M urea. Furthermore, COS cells transfected with CAG-expanded AR cDNA generate an aberrant, nuclear-associated 75 kDa derivative containing the Gln-expanded tract. They are also twice as likely to die by 24 h apoptotically than those transfected with normal AR cDNA. Our data support the notion that an unconventional derivative of the Gln- expanded AR is a component of the proximate motor neuronopathic agent in spinobulbar muscular atrophy. They also focus attention on two ways in which neuronotoxic derivatives may originate from various Gln-expanded proteins: (i) generation of an unusual derivative that is pathogenic de novo ; and (ii) the toxic accumulation of a normal derivative because of an inability to dispose of it.
authors.affiliation: Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote Sainte Catherine Road, Montreal, Quebec H3T 1E2, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Abdullah
authors.forename: M A
authors.initials: MA
authors.lastname: Trifiro
authors.forename: V
authors.initials: V
authors.lastname: Panet-Raymond
authors.forename: C
authors.initials: C
authors.lastname: Alvarado
authors.forename: S
authors.initials: S
authors.lastname: de Tourreil
authors.forename: D
authors.initials: D
authors.lastname: Frankel
authors.forename: H M
authors.initials: HM
authors.lastname: Schipper
authors.forename: L
authors.initials: L
authors.lastname: Pinsky
mesh_terms: D000818:Animals; D019556:COS Cells; D002470:Cell Survival / Q000528:radiation effects; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism; D010455:Peptides; D014176:Protein Biosynthesis; D011817:Rabbits; D011944:Receptors, Androgen / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis; D012156:Reticulocytes / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D018911:Trinucleotide Repeats; D014466:Ultraviolet Rays
chemical_list: D010455:Peptides; D011944:Receptors, Androgen; D011994:Recombinant Proteins; C097188:polyglutamine